Cardiac arrhythmias continue to be a leading cause of death and disability. Despite this alarming fact, a noninvasive imaging modality (analogous to CT or MRI) for cardiac electrophysiology and arrhythmia has not been available for clinical diagnosis and guidance of therapy. Importantly, such imaging modality is also greatly needed for the study of arrhythmia mechanisms in humans, where the arrhythmic substrate and disease processes differ considerably from that in experimental animal models. During the current grant period, we have developed, implemented and validated a novel noninvasive imaging modality (Electrocardiographic Imaging, ECGI) and demonstrated its successful application in humans. In the next period of support, we will apply ECGI to study arrhythmic substrates and arrhythmia mechanisms in humans. Goals for the next period are: (1) To characterize the electrophysiological substrate associated with anatomical scars in post myocardial infarction (post-MI) patients. (2) To image scar-related ventricular tachyarrhythmias (VT) in these patients. (3) To image activation and repolarization in patients with the Wolff-Parkinson-White (WPW) syndrome before and after accessory pathway ablation, and to study cardiac memory in these patients. (4) To image the electrophysiological substrate in non-ischemic dilated cardiomyopathy patients and to study pacing-induced changes during cardiac resynchronization therapy (CRT). (5) To extend the ECGI method (presently formulated for epicardial reconstructions) to include the endocardial surface of the heart. Public Health Relevance: An estimated 400,000 Americans die each year from erratic heart rhythms, and many more are disabled (estimated annual fatalities worldwide is seven million). The proposed research is aimed at the continued development of a noninvasive imaging modality for cardiac arrhythmias (Electrocardiographic Imaging, ECGI) and its application in the study of arrhythmia properties and mechanisms in humans.